Abstract
Atrial fibrillation (AF) affects 1.5–2.0% of the population in the developed world. Projected data from population-based studies in the US indicate that the number of adults with AF will swell by 2.5–3.0-fold by 2050. Despite advances in pharmacological and nonpharmacological therapies for rhythm or rate control in patients with AF, primary prevention with 'upstream' therapy and risk factor modification is likely to produce a far greater effect in the general population than specific interventions. Rapidly developing experimental work has provided new insights into AF pathophysiology that will lead to new mechanism-based therapies. Agents targeting inflammation, oxidative injury, atrial myocyte metabolism, extracellular matrix remodeling, and fibrosis, have theoretical advantages as novel therapeutic strategies. Angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, β-blockers, statins, and omega-3 polyunsaturated fatty acids have shown antiarrhythmic potential, over and above any effect related to the treatment of underlying heart disease. These agents could be exploited to prevent or delay atrial remodeling in patients with AF, even in the absence of routine indications for such therapy. This Review provides a contemporary evidence-based insight into the possible preventive and reverse remodeling roles of statins and polyunsaturated fatty acids in AF.
Key Points
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The high lifetime risk for atrial fibrillation (AF) and increased incidence with longevity underscore the important public-health burden posed by AF
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Specific interventions for rhythm or rate control are modestly effective in some patients, but are not consistently applied to all those at risk of AF because of adverse effects, limited availability and increased costs
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Recently, atrial stretch, angiotensin II and inflammation have been recognized as key elements in atrial remodeling and the formation of the substrate for AF
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Experimental studies using rapid atrial pacing, sterile pericarditis and heart failure models of AF have convincingly demonstrated that treatment with renin–angiotensin system antagonists, statins and specific anti-inflammatory agents, such as corticosteroids, reduces the amount of atrial fibrosis and counteracts changes in electrical properties of the atrial myocardium associated with sustained AF
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A raft of therapies with 'upstream' effects are now being actively investigated and results are promising so far; the antiarrhythmic potential of statins and polyunsaturated fatty acids probably goes beyond any effect related to the treatment of underlying heart disease
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It is highly likely that the clinical approach to AF management in the general population will change substantially in the near future
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References
Lloyd-Jones DM et al. (2004) Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 110: 1042–1046
Heeringa J et al. (2006) Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 27: 949–953
Miyasaka Y et al. (2006) Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 114: 119–125
Savelieva I et al. (2000) Clinical relevance of silent atrial fibrillation: prevalence, prognosis, quality of life, and management. J Interv Card Electrophysiol 4: 369–382
Camm AJ (2005) Atrial fibrillation—an end to the epidemic? Circulation 112: iii
Allessie MA et al. (2001) Pathophysiology and prevention of atrial fibrillation. Circulation 103: 769–777
Ravelli F (2003) Mechano-electric feedback and atrial fibrillation. Prog Biophys Mol Biol 82: 137–149
Kalifa J et al. (2003) Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation. Circulation 108: 668–671
Bode F et al. (2000) Gadolinium decreases stretch-induced vulnerability to atrial fibrillation. Circulation 101: 2200–2205
Bode F et al. (2001) Tarantula peptide inhibits atrial fibrillation. Nature 409: 35–36
Cardin S et al. (2003) Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways. Cardiovasc Res 60: 315–325
Mathew JP et al. (2004) Investigators of the Ischemia Research and Education Foundation; Multicenter Study of Perioperative Ischemia Research Group: a multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 291: 1720–1729
Frustaci A et al. (1997) Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96: 1180–1184
Kumagai K et al. (2004) The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model. Cardiovasc Res 62: 105–111
Shiroshita-Takeshita A et al. (2004) The effect of simvastatin and antioxidant vitamins on atrial fibrillation—promotion by atrial tachycardia remodeling in dogs. Circulation 110: 2313–2319
Shiroshita-Takeshita A et al. (2006) Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs. Cardiovasc Res 69: 865–875
Dernellis J et al. (2005) Effect of C-reactive protein reduction on paroxysmal atrial fibrillation. Am Heart J 150: 1064e
Dernellis J et al. (2004) Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur Heart J 25: 1100–1117
Halonen J et al. (2007) Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. JAMA 297: 1562–1567
Ishii Y et al. (2005) Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation 111: 2881–2888
Tselentakis E et al. (2006) Inflammation effects on the electrical properties of atrial tissue and inducibility of postoperative atrial fibrillation. J Surg Res 135: 68–75
Ryu K et al. (2007) Effects of sterile pericarditis on connexins 40 and 43 in the atria—correlation with abnormal conduction and atrial arrhythmias. Am J Physiol Heart Circ Physiol 923: H1231–H1241
Wetzel U et al. (2005) Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart 91: 166–170
Gaudino M et al. (2003) The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation: is atrial fibrillation an inflammatory complication. Circulation 108 (Suppl II): II-195–II-199
Psychari SN et al. (2005) Relation of elevated C-reactive protein and interleukin-6 levels to left atrial size and duration of episodes in patients with atrial fibrillation. Am J Cardiol 95: 764–767
Wazni O et al. (2005) C reactive protein concentration and recurrence of atrial fibrillation after electrical cardioversion. Heart 91: 1303–1305
Chung MK et al. (2001) C-reactive protein elevation in patients with atrial arrhythmias. Circulation 104: 2886–2891
Zacks ES et al. (2006) Association of markers of inflammation with new onset atrial fibrillation in a population-based sample: the Strong Heart Study [abstract]. Circulation 114 (Suppl II): II-678
Aviles RJ et al. (2003) Inflammation as a risk factor for atrial fibrillation. Circulation 108: 3006–3010
Ellinor PT et al. (2006) C-Reactive protein in lone atrial fibrillation. Am J Cardiol 97: 1346–1350
Liu T et al. (2007) Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: a meta-analysis. J Am Coll Cardiol 49: 1642–1648
White CW et al. (1982) The effects of atrial fibrillation on atrial pressure-volume and flow relationships. Circ Res 51: 205–215
Mihm MJ et al. (2001) Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 104: 174–180
Dudley SC Jr et al. (2005) Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 112: 1266–1273
Carnes CA (2001) Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 89: E32–E38
Shiroshita-Takeshita A et al. (2003) Differential efficacy of drugs with antioxidant properties on atrial fibrillation promotion by atrial tachycardia remodeling in dogs [abstract]. Circulation 108 (Suppl): IV-148
Anné W et al. (2005) Matrix metalloproteinases and atrial remodeling in patients with mitral valve disease and atrial fibrillation. Cardiovasc Res 67: 655–666
Xu J et al. (2004) Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation. Circulation 109: 363–368
Nakano Y et al. (2004) Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation. J Am Coll Cardiol 43: 818–825
Hoit BD (2003) Matrix metalloproteinases and atrial structural remodeling. J Am Coll Cardiol 42: 345–347
Mukherjee R et al. (2006) Selective induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation. Am J Cardiol 97: 532–537
Kirstein M et al. (1995) Nitric oxide regulates the calcium current in isolated human atrial myocytes. J Clin Invest 95: 794–802
Kubota I et al. (2000) Increased susceptibility to development of triggered activity in myocytes from mice with targeted dirsuption of endothelial nitric oxide synthase. J Mol Cell Cardiol 32: 1239–1248
Fatini C et al. (2006) Analysis of min K and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation. Eur Heart J 27: 1712–1718
Skalidis EI et al. (2007) Endothelial cell function during atrial fibrillation and after restoration of sinus rhythm. Am J Cardiol 99: 1258–1262
Lenaerts I et al. (2006) Nitric oxide prevents atrial tachycardia induced electrical remodeling in a sheep model [abstract]. Heart Rhythm 3 (Suppl): S180
Marín F et al. (2006) Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol 97: 55–60
Patti G et al. (2006) Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study. Circulation 114: 1455–1461
Young-Xu Y et al. (2003) Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 92: 1379–1383
Siu CW et al. (2003) Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 92: 1343–1345
Hanna IR et al. (2006) Lipid-lowering drug use is associated with reduced prevalence of atrial fibrillation in patients with left ventricular systolic dysfunction. Heart Rhythm 3: 881–886
Dickinson MG et al. (2006) Statin therapy was associated with reduced atrial fibrillation and flutter in heart failure patients in SCD-HeFT [abstract]. Heart Rhythm 3 (Suppl): S49
Tveit A et al. (2004) Analysis of pravastatin to prevent recurrence of atrial fibrillation after electrical cardioversion. Am J Cardiol 93: 780–782
Schwartz GG et al. (2004) Effect of intensive statin treatment on the occurrence of atrial fibrillation after acute coronary syndrome: an analysis of the MIRACL trial [abstract]. Circulation 110 (Suppl III): III-740
Ozaydin M et al. (2007) Statin use before by-pass surgery decreases the incidence and shortens the duration of postoperative atrial fibrillation. Cardiology 107: 117–121
Richter B et al. (2007) Therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins: no effect on ablation outcome after ablation of atrial fibrillation. Am Heart J 153: 113–119
Tsai CT et al. (2007) Atorvastatin prevents atrial fibrillation in patients with implantation of a pacemaker: a prospective randomized trial [abstract]. Heart Rhythm 4 (Suppl 5): S119
Amit G et al. (2006) Association of statin therapy and the risk of atrial fibrillation in patients with a permanent pacemaker. Clin Cardiol 29: 249–252
Ramani G et al. (2007) Comparison of frequency of new-onset atrial fibrillation or flutter in patients on statins versus not on statins presenting with suspected acute coronary syndrome. Am J Cardiol 100: 404–405
Al Chekakie MO et al. (2007) The effects of statins and renin-angiotensin system blockers on atrial fibrillation recurrence following antral pulmonary vein isolation. J Cardiovasc Electrophysiol 18: 942–946
Garcia-Fernandez A et al. (2006) Effect of statins on preventing recurrence of atrial fibrillation after electrical cardioversion. Am J Cardiol 98: 1299–1300
Kotlewski A et al. (2006) Prevalence of atrial fibrillation and flutter by different HMG-CoA reductase inhibitors and doses in heart failure [abstract]. J Am Coll Cardiol 47 (Suppl A): 61A
Ninio DM et al. (2005) Dietary fish oil protects against stretch-induced vulnerability to atrial fibrillation in a rabbit model. J Cardiovasc Electrophysiol 16: 1189–1194
Leaf A et al. (2003) Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 107: 2646–2652
Calder PC (2006) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83 (Suppl): S1505–S1519
Davidson MH (2006) Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids. Am J Cardiol 98: 27i–33i
Laurent G et al. (2007) Omega-3 polyunsaturated fatty acids attenuate atrial structural remodeling and prevent AF inducibility [abstract]. Heart Rhythm 4 (Suppl 5): S9
Jahangiri A et al. (2000) Termination of asynchronous contractile activity in rat atrial myocytes by n-3 polyunsaturated fatty acids. Mol Cell Biochem 206: 33–41
Da Cunha DN et al. (2007) n-3 (omega-3) polyunsaturated fatty acids prevent acute atrial electrophysiological remodeling. Br J Pharmacol 150: 281–285
Calò L et al. (2005) n-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol 45: 1723–1728
Mozaffarian D et al. (2004) Fish intake and risk of incident atrial fibrillation. Circulation 110: 368–373
Frost L et al. (2005) n-3 Fatty acids consumed from fish and risk of atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. Am J Clin Nutr 81: 50–54
Aizer A et al. (2006) Relationship between fish consumption and the development of atrial fibrillation in men [abstract]. Heart Rhythm 3 (Suppl 1): S5
Brouwer IA et al. (2006) Intake of very long-chain n-3 fatty acids from fish and incidence of atrial fibrillation. The Rotterdam Study. Am Heart J 151: 857–862
Erdogan A et al. (2007) Omega AF study [L] polyunsaturated fatty acids (PUFA) for prevention of atrial fibrillation relapse after successful external cardioversion [abstract]. Heart Rhythm 4 (Suppl 5): S185–S186
Brouwer IA et al. (2006) Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 295: 2613–2619
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Savelieva, I., Camm, J. Statins and polyunsaturated fatty acids for treatment of atrial fibrillation. Nat Rev Cardiol 5, 30–41 (2008). https://doi.org/10.1038/ncpcardio1038
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DOI: https://doi.org/10.1038/ncpcardio1038
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